This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. In the presence of specialized proteins or peptides, a biological membrane can spontaneously restructure itself to allow communication between the intracellular side and the extracellular side. To accomplish this, nature uses synergistic combinations of interactions, such as electrostatics, hydrogen bonding, hydrophobic, and geometric effects. Such interactions are known to be important for molecular ?hole punchers? such as cell penetrating peptides that cross cell membranes, and membrane?active antimicrobials that permeate cell membranes. The molecular mechanisms of these peptides are not fully understood at present. Moreover, it is not understood why cell penetrating peptides can form pores without killing cells, whereas antimicrobials form pores that are designed to kill cells. In this proposal, we examine prototypical antimicrobial peptides (alpha?, beta?, and theta-defensins) and arginine?rich cell penetrating peptides. Both of these arginine?rich prototypical systems have potential for translational impact: Defensins constitute one of the two main classes of antimicrobial peptides in mammals, and cell penetrating peptides are used broadly for controlled drug delivery in the biotechnology industry. A fundamental understanding of design rules governing these peptides will have a transformative impact in the design of antimicrobials and cell penetrating peptides, as well as soft matter physics and colloid science.